Systems and methods for determination of pharmaceutical fluid injection protocols based on x-ray tube voltage

ABSTRACT

A system for patient imaging is provided. The system includes an imaging system and a parameter generator to determine parameters of at least a first phase of an injection procedure. The imaging system includes a scanner that has at least one x-ray tube. The parameter generator is programmed to determine at least one of the parameters on the basis of a voltage to be applied to the at least one x-ray tube during an imaging procedure. A method of controlling an injector system is also provided, and the method includes determining injection parameters, at least one of which is determined on the basis of a voltage to be applied to an x-ray tube during the imaging procedure, as well as controlling the injector system at least in part on the basis of the determined injection parameters.

The present application is a 35 U.S.C. § 120 continuation application ofU.S. patent application Ser. No. 14/401,330, filed Nov. 14, 2014, whichis a 35 U.S.C. § 371 national phase application of PCT/US12/37744, filedon May 14, 2012, the entire contents of which are incorporated byreference herein.

RELATED APPLICATIONS

This application contains subject matter that may be related to thatdisclosed and/or claimed in U.S. Pat. No. 7,925,330, filed on Mar. 27,2007, United States Patent Application Publication Numbers 2007/0213662,filed on Mar. 27, 2008; 2007/0255135, filed Mar. 27, 2007; 2008/0097197,filed Mar. 22, 2007; 2010/0030073, filed on Jun. 12, 2009; 2010/0113887,filed on Jun. 15, 2009; 2010-0204572, filed on Jan. 15, 2010; andInternational Patent Application Publication Numbers WO/2006/058280(International Patent Application No. PCT/US05/042891), filed on Nov.23, 2005, and WO/2006/055813 (International Patent Application No.PCT/US2005/041913), filed on Nov. 16, 2005, the disclosures of which areincorporated herein by reference and made a part hereof.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention is related to devices, systems and methods forfluid delivery, and, particularly, to devices, systems and methods fordelivery of a pharmaceutical fluid to a patient, and, especially fordelivery of a contrast medium to a patient during a medical injectionprocedure for diagnostic and/or therapeutic reasons.

Description of Related Art

The following information is provided to assist the reader to understandthe invention disclosed below and the environment in which it willtypically be used. The terms used herein are not intended to be limitedto any particular narrow interpretation unless clearly stated otherwisein this document. References set forth herein may facilitateunderstanding of the present invention or the background of the presentinvention. The disclosure of all references cited herein is incorporatedby reference.

The administration of contrast medium with, for example, a powerinjector for radiological exams typically starts with the clinicianfilling an empty, disposable syringe with a certain volume of contrastagent pharmaceutical. In other procedures, a syringe pre-filled withcontrast agent may be used. The clinician then determines a volumetricflow-rate and a volume of contrast to be administered to the patient toenable a diagnostic image. An injection of saline solution, having avolume and flow rate determined by the operator, often follows theadministration of contrast agent into the veins or arteries. A number ofcurrently available injectors allow for the operator to program aplurality of discrete phases of volumetric flow rates and volumes todeliver. For example, the SPECTRIS SOLARIS® and STELLANT® injectorsavailable from MEDRAD, INC., a business of Bayer HealthCare, provide forentry of up to and including six discrete pairs or phases of volumetricflow rate and volume for delivery to a patient (for example, forcontrast and/or saline). Such injectors and injector control protocolsfor use therewith are disclosed, for example, in U.S. Pat. No. 6,643,537and Published U.S. Patent Application Publication No. 2004/0064041,assigned to the assignee of the present invention, the disclosures ofwhich are incorporated herein by reference. The values or parameterswithin the fields for such phases are generally entered manually by theoperator for each type of procedure and for each patient undergoing aninjection/imaging procedure. Alternatively, earlier manually enteredvalues of volume and flow rate can be stored and later recalled from thecomputer memory. However, the manners in which such parameters are to bedetermined and tailored for a specific procedure for a specific patientare not well developed.

In this regard, differences in contrast dosing requirements fordifferent patients during imaging and other procedures have beenrecognized. For example, U.S. Pat. No. 5,840,026, assigned to theassignee of the present invention, the disclosure of which isincorporated herein by reference, discloses devices and methods tocustomize the injection to the patient using patient specific dataderived before or during an injection. Although differences in dosingrequirements for medical imaging procedures based upon patientdifferences have been recognized, conventional medical imagingprocedures continue to use pre-set doses or standard delivery protocolsfor injecting contrast media during medical imaging procedures. Giventhe increased scan speed of recently available CT scanners includingMDCT (or MSCT) scanners, single phase injections are dominant overbiphasic or other multiphasic injections in regions of the world wheresuch fast scanners are used. Although using standard, fixed orpredetermined protocols (whether uniphasic, biphasic or multiphasic) fordelivery simplifies the procedure, providing the same amount of contrastmedia to different patients under the same protocol can produce verydifferent results in image contrast and quality. Furthermore, with theintroduction of the newest MDCT scanners, an open question in clinicalpractice and in the CT literature is whether the standard contrastprotocols used with single-slice, helical scanners will translate wellto procedures using the MDCT machines. See, for example, Cademartiri, F.and Luccichenti, G., et al., “Sixteen-row multi-slice computedtomography: basic concepts, protocols, and enhanced clinicalapplications.” Semin Ultrasound CT MR 25(1): 2-16 (2004).

A few studies have attempted quantitative analyses of the injectionprocess during CT angiography (CTA) to improve and predict arterialenhancement. For example, Bae and coworkers developed pharmacokinetic(PK) models of the contrast behavior and solved the coupled differentialequation system with the aim of finding a driving function that causesthe most uniform arterial enhancement. K. T. Bae, J. P. Heiken, and J.A. Brink, “Aortic and hepatic contrast medium enhancement at CT. Part I.Prediction with a computer model,” Radiology, vol. 207, pp. 647-55(1998); K. T. Bae, “Peak contrast enhancement in CT and MR angiography:when does it occur and why? Pharmacokinetic study in a porcine model,”Radiology, vol. 227, pp. 809-16 (2003); K. T. Bae et al., “MultiphasicInjection. Method for Uniform Prolonged Vascular Enhancement at CTAngiography: Pharmacokinetic Analysis and Experimental Porcine Method,”Radiology, vol. 216, pp. 872-880 (2000); U.S. Pat. Nos. 5,583,902,5,687,208, 6,055,985, 6,470,889 and 6,635,030, the disclosures of whichare incorporated herein by reference. An inverse solution to a set ofdifferential equations of a simplified compartmental model set forth byBae et al. indicates that an exponentially decreasing flow rate ofcontrast medium may result in optimal/constant enhancement in a CTimaging procedure. However, the injection profiles computed by inversesolution of the PK model are profiles not readily realizable by most CTpower injectors without major modification.

In another approach, Fleischmann and coworkers treated thecardiovascular physiology and contrast kinetics as a “black box” anddetermined its impulse response by forcing the system with a short bolusof contrast (approximating a unit impulse). In that method, one performsa Fourier transform on the impulse response and manipulates thistransfer function estimate to determine an estimate of a more optimalinjection trajectory than practiced previously. D. Fleischmann and K.Hittmair, “Mathematical analysis of arterial enhancement andoptimization of bolus geometry for CT angiography using the discreteFourier transform,” J. Comput. Assist Tomogr., vol. 23, pp. 474-84(1999), the disclosure of which is incorporated herein by reference.

Uniphasic administration of contrast agent (typically, 100 to 150 mL ofcontrast at one flow rate) results in a non-uniform enhancement curve.See, for example, D. Fleischmann and K. Hittmair, supra; and K. T. Bae,“Peak contrast enhancement in CT and MR angiography: when does it occurand why? Pharmacokinetic study in a porcine model,” Radiology, vol. 227,pp. 809-16 (2003), the disclosures of which are incorporated herein byreference. Fleischmann and Hitmair thus presented a scheme thatattempted to adapt the administration of contrast agent into a biphasicinjection tailored to the individual patient with the intent ofoptimizing imaging of the aorta. A fundamental difficulty withcontrolling the presentation of CT contrast agent is that hyperosmolardrug diffuses quickly from the central blood compartment. Additionally,the contrast is mixed with and diluted by blood that does not containcontrast.

Fleischmann proscribed that a small bolus injection, a test bolusinjection, of contrast agent (16 ml of contrast at 4 ml/s) be injectedprior to the diagnostic scan. A dynamic enhancement scan was made acrossa vessel of interest. The resulting processed scan data (test scan) wasinterpreted as the impulse response of the patient/contrast mediumsystem. Fleischmann derived the Fourier transform of the patienttransfer function by dividing the Fourier transform of the test scan bythe Fourier transform of the test injection. Assuming the system was alinear time invariant (LTI) system and that the desired output timedomain signal was known (a flat diagnostic scan at a predefinedenhancement level) Fleischmann derived an input time signal by dividingthe frequency domain representations of the desired output by that ofthe patient transfer function. Because the method of Fleischmann et al.computes input signals that are not realizable in reality as a result ofinjection system limitations (for example, flow rate limitations), onemust truncate and approximate the computed continuous time signal.

In addition, to control a powered injector to provide a desired timeenhancement curve, the operation of a powered injector should becarefully controlled to ensure the safety of the patient. For example,it is desirable not to exceed a certain fluid pressure during aninjection procedure. In addition to potential hazards to the patient(for example, vessel damage) and potential degradation of the diagnosticand/or therapeutic utility of the injection fluid, excessive pressurecan lead to equipment failure. Disposable syringes and other fluid pathcomponents (sometimes referred to collectively as a “disposable set”)are typically fabricated from plastics of various burst strengths. Ifthe injector causes pressure in the fluid path to rise above the burststrength of a disposable fluid path element, the fluid path element willfail.

In addition to problems of control with current injector systems, manysuch systems lack convenience and flexibility in the manner in which theinjector systems must be operated. In this regard, the complexity ofmedical injection procedures and the hectic pace in all facets of thehealth care industry place a premium on the time and skills of anoperator.

Although advances have been made in the control of fluid deliverysystems to, for example, provide a desirable time enhancement curve andto provide for patient safety, it remains desirable to develop improveddevices, systems, and method for delivery of fluids to a patient.

SUMMARY OF THE INVENTION

In one aspect of the invention, provided is a system for patient imagingincluding an imaging system and a parameter generator to determineparameters of at least a first phase of an injection procedure, whereinthe imaging system comprises a scanner comprising at least one x-raytube and wherein the parameter generator is programmed to determine atleast one of the parameters on the basis of a voltage to be applied tothe at least one x-ray tube during an imaging procedure. The scanner maybe a CT scanner, which may be programmable to operate at different x-raytube voltages.

In certain embodiments, the parameter generator of the system can be incommunicative connection with the imaging system. In certainembodiments, the parameter generator can be integrated into the imagingsystem.

In some non-limiting embodiments, the system can further include aninjector system, and the injector system can include at least onepressurizing mechanism, at least one fluid container operably associatedwith the at least one pressurizing mechanism, one of the fluidcontainers adapted to contain a contrast enhancing agent and one of thefluid containers adapted to contain a diluent, and a controller operablyassociated with the at least one pressurizing mechanism.

In certain embodiments, the parameter generator can be in communicativeconnection with at least one of the imaging system and the controller ofthe injector system, and in certain embodiments, the parameter generatorcan be integrated into the injector system.

In some non-limiting embodiments, the parameter generator can beprogrammed to determine at least one of a volume of a pharmaceuticalfluid to be injected during at least the first phase and a flow rate ofthe pharmaceutical fluid to be injected during at least the first phaseon the basis of the voltage to be applied to the at least one x-ray tubeduring the imaging procedure. The pharmaceutical fluid may include acontrast enhancing agent.

In certain non-limiting embodiments, the parameter generator can beprogrammed to determine the volume of the pharmaceutical fluid to beinjected during at least the first phase according to the formula:V₁=weight*X*Y, wherein V₁ is the volume of the pharmaceutical fluid, Xis a function of patient weight and x-ray tube voltage, and Y is afunction of the concentration of a contrast enhancing agent in thepharmaceutical fluid. The parameter generator may be programmed todetermine X for a particular patient weight from a look-up table whereinX is set forth as a function of patient weight and the voltage to beapplied to the at least one x-ray tube during the imaging procedure.

In some non-limiting embodiments, the parameter generator can beprogrammed to determine at least a first flow rate of the pharmaceuticalfluid by dividing V₁ by an injection duration of the first phase. Theparameter generator may be programmed to determine the injectionduration on the basis of one or more criteria inputted by an operator,which criteria can include at least an identification of a body regionto be imaged during the imaging procedure.

In certain non-limiting embodiments, the parameter generator can befurther programmed to determine a volume V₂ of pharmaceutical fluid tobe delivered in at least a second phase of the injection procedure inwhich both the pharmaceutical fluid and a diluent are to be delivered.

In some non-limiting embodiments, the parameter generator can beprogrammed to determine the volume of the pharmaceutical fluid to beinjected during at least the first phase by adjusting a volume parameterof a baseline injection protocol. Data representing the baselineinjection protocol can exists in memory of the system or accessible tothe system. The parameter generator can also be programmed to determinethe baseline injection protocol on the basis of one or more criteriainputted by an operator. In certain embodiments, the parameter generatorcan be programmed to determine the volume of the pharmaceutical fluid tobe injected during at least the first phase by applying a tube voltagemodification factor to the volume parameter of the baseline injectionprotocol.

In some non-limiting embodiments, the parameter generator can beprogrammed to determine the flow rate of the pharmaceutical fluid to beinjected during at least the first phase by adjusting a flow rateparameter of a baseline injection protocol. Data representing thebaseline injection protocol can exists in memory of the system oraccessible to the system. The parameter generator can also be programmedto determine the baseline injection protocol on the basis of one or morecriteria inputted by an operator. In certain embodiments, the parametergenerator can be programmed to determine the flow rate of thepharmaceutical fluid to be injected during at least the first phase byapplying a tube voltage modification factor to the flow rate parameterof the baseline injection protocol.

In another aspect, provided is a parameter generator for use in animaging system comprising a scanner comprising at least one x-ray tube,wherein the parameter generator is programmed to determine parameters ofat least a first phase of an injection procedure including at least oneparameter on the basis of a voltage to be applied to the at least onex-ray tube during an imaging procedure.

In another non-limiting embodiment, provided is a method of controllingan injector system for delivering a pharmaceutical fluid to a patient aspart of an imaging procedure, the injector system in operativeconnection with an imaging system comprising a scanner comprising atleast one x-ray tube. The steps of the method include: determining,using a parameter generator, injection parameters of at least a firstphase of an injection procedure, wherein at least one of the injectionparameters is determined on the basis of a voltage to be applied to theat least one x-ray tube during the imaging procedure; and controllingthe injector system at least in part on the basis of the determinedinjection parameters.

In some non-limiting embodiments of the method, the injection parametersthat are determined include at least one of a volume of thepharmaceutical fluid to be injected during at least the first phase ofthe injection procedure and a flow rate of the pharmaceutical fluid tobe injected during at least the first phase of the injection procedure.The volume of the pharmaceutical fluid to be injected during at leastthe first phase can be determined according to the formula:V₁=weight*X*Y, wherein V₁ is the volume of the pharmaceutical fluid, Xis a function of patient weight and x-ray tube voltage, and Y is afunction of the concentration of a contrast enhancing agent in thepharmaceutical fluid. In certain embodiments, X is determined for aparticular patient weight from a look-up table wherein X is set forth asa function of patient weight and the voltage to be applied to the atleast one x-ray tube during the imaging procedure.

In certain non-limiting embodiments of the method, at least a first flowrate of the pharmaceutical fluid is determined by dividing V₁ by aninjection duration of the first phase. The injection duration of thefirst phase can be inputted by an operator using a graphical userinterface. The injection duration can also be determined by theparameter generator on the basis of one or more criteria inputted by anoperator.

In some non-limiting embodiments of the method, the volume of thepharmaceutical fluid to be injected during at least the first phase isdetermined by adjusting a volume parameter of a baseline injectionprotocol. Data representing the baseline injection protocol can berecalled from memory associated with or accessible by at least one ofthe injector system, the imaging system, and the parameter generator.The baseline injection protocol may also be determined on the basis ofone or more criteria inputted by an operator. The volume of thepharmaceutical fluid to be injected during at least the first phase ofthe injection procedure can be determined by applying a tube voltagemodification factor to the volume parameter of the baseline injectionprotocol.

In certain non-limiting embodiments of the method, the flow rate of thepharmaceutical fluid to be injected during at least the first phase isdetermined by adjusting a flow rate parameter of a baseline injectionprotocol. Data representing the baseline injection protocol can berecalled from memory associated with or accessible by at least one ofthe injector system, the imaging system, and the parameter generator.The baseline injection protocol can be determined on the basis of one ormore criteria inputted by an operator. The flow rate of thepharmaceutical fluid to be injected during at least the first phase canbe determined by applying a tube voltage modification factor to the flowrate parameter of the baseline injection protocol.

In some non-limiting embodiments of the method, the method can furtherinclude the step of populating the determined injection parameters on agraphical user interface associated with at least one of the injectorsystem and the imaging system.

In another aspect, provided is a method of generating an injectionprotocol for use with an injector system in operative connection with animaging system comprising a scanner comprising at least one x-ray tube,the method including the step of determining, using a parametergenerator, injection parameters of at least a first phase of aninjection procedure, wherein at least one of the injection parameters isdetermined on the basis of a voltage to be applied to the at least onex-ray tube during an imaging procedure.

The present invention, along with the attributes and attendantadvantages thereof, will best be appreciated and understood in view ofthe following detailed description taken in conjunction with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an embodiment of a multi-phasic Graphical UserInterface (GUI) for use in setting forth parameters for a plurality ofphases for a two-syringe injector also illustrated in FIG. 1.

FIG. 2 illustrates an embodiment of a graphical interface from which anoperator can choose a vascular region of interest for imaging.

FIG. 3 illustrates an embodiment of a graphical interface from which anoperator can enter variables related to a particular imaging procedure.

FIG. 4 illustrates an embodiment of a graphical interface which presentsan operator with a computed injection protocol.

FIG. 5 illustrates a simulated histogram in the right heart compartment.

FIG. 6 illustrates the total contrast material delivered to simulatedpatients for different weight values and tube voltage values accordingto contrast delivery protocols generated using an embodiment of aparameter generation system.

FIG. 7 illustrates the mean flow rate of contrast material delivered tosimulated patients for different weight values and tube voltage valuesaccording to contrast delivery protocols generated using an embodimentof a parameter generation system.

FIG. 8 illustrates the mean right heart (RH) enhancement value achievedin simulated patients for different weight values and tube voltagevalues according to contrast delivery protocols generated using anembodiment of a parameter generation system.

FIG. 9 illustrates the distribution of patient weight of a patientsampling.

FIG. 10 illustrates the distribution of patient height of the patientsampling of FIG. 9.

FIG. 11 illustrates the distribution of patient age of the patientsampling of FIG. 9.

FIG. 12 illustrates the average flow rate at different patient weightsfor the patient sampling of FIG. 9 according to contrast deliveryprotocols generated at different tube voltages using an embodiment of aparameter generation system.

FIG. 13 illustrates the mean total contrast volume delivered atdifferent patient weights for the patient sampling of FIG. 9 accordingto contrast delivery protocols generated at different tube voltagesusing an embodiment of a parameter generation system.

FIG. 14 illustrates the mean enhancement value in the patient samplingof FIG. 9 for different scan durations according to contrast deliveryprotocols generated at different tube voltage values using an embodimentof a parameter generation system.

FIG. 15 illustrates the mean flow rate of contrast volume delivered atdifferent scan durations for the patient sampling of FIG. 9 according tocontrast delivery protocols generated at different tube voltage valuesusing an embodiment of a parameter generation system.

FIG. 16 illustrates the mean enhancement value in the patient samplingof FIG. 9 at different injection durations according to contrastdelivery protocols generated at different tube voltage values using anembodiment of a parameter generation system.

FIG. 17 illustrates an embodiment of a graphical interface from which anoperator can choose a vascular region of interest and baseline protocolfor imaging.

FIG. 18 illustrates another embodiment of a graphical interface fromwhich an operator can choose a vascular region of interest and baselineprotocol for imaging.

FIG. 19 illustrates an embodiment of a graphical interface from which anoperator can choose a tube voltage value.

FIG. 20 illustrates an embodiment of a graphical interface from which anoperator can choose a tube voltage value along with other variables ofan injection procedure.

FIG. 21 illustrates another portion of a graphical interface for usewith an embodiment of a parameter generation system.

FIG. 22 illustrates another portion of a graphical interface for usewith an embodiment of a parameter generation system.

FIG. 23 illustrates an embodiment of a graphical interface whichpresents an operator with a computed injection protocol.

FIG. 24 illustrates another embodiment of a graphical interface whichpresents an operator with a computed injection protocol.

FIGS. 25-27 illustrate examples of the methodology exemplified invarious embodiments of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As used herein with respect to an injection procedure, the term“protocol” refers to a group of parameters such as flow rate, volume tobe injected, injection duration, etc. that define the amount of fluid(s)to be delivered to a patient during an injection procedure. Suchparameters can change over the course of the injection procedure. Asused herein, the term “phase” refers generally to a group of parametersthat define the amount of fluid(s) to be delivered to a patient during aperiod of time (or phase duration) that can be less than the totalduration of the injection procedure. Thus, the parameters of a phaseprovide a description of the injection over a time instancecorresponding to the time duration of the phase. An injection protocolfor a particular injection procedure can, for example, be described asuniphasic (a single phase), biphasic (two phases) or multiphasic (two ormore phases, but typically more than two phases). Multiphasic injectionsalso include injections in which the parameters can change continuouslyover at least a portion of the injection procedure.

In several embodiments, an injector system (such as a dual syringeinjector system 100 as illustrated in FIG. 1 and as, for example,disclosed in U.S. Pat. No. 6,643,537 and U.S. Patent ApplicationPublication No. 2004/0064041) may be used to implement the conceptsdescribed in detail herein, and typically includes two fluid deliverysources (sometimes referred to as source “A” and source “B” herein, suchas syringes) that are operable to introduce a first fluid and/or asecond fluid (for example, contrast medium, saline/diluent, etc.) to apatient independently (for example, simultaneously, simultaneously indifferent volumetric flow proportion to each other, or sequentially orsubsequent to each other (that is, A then B, or B then A)).

In the embodiment of FIG. 1, source A is in operative connection with apressurizing mechanism such as a drive member 110A, and source B is inoperative connection with a pressurizing mechanism such as a drivemember 110B. Source A and source B can each be, for example, a fluidcontainer. The injector system 100 includes a controller 200 inoperative connection with injector system 100 and drive members 110A and110B that is operable to control the operation of drive members 110A and110B to control injection of fluid A (for example, contrast medium) fromsource A and injection of fluid B (for example, saline/diluent) fromsource B, respectively. Controller 200 can, for example, include a userinterface comprising a display 210. Controller 200 can also include aprocessor 220 (for example, a digital microprocessor as known in theart) in operative connection with a memory 230. The system can furtherinclude an imaging system 300. Imaging system 300 can, for example, be aComputed Tomography (CT) system or another tomographic imaging system.The injector system 100 can be in communicative connection with imagingsystem 300, and one, a plurality or all the components of the injectorsystem 100 and imaging system 300 can be integrated into a singledevice.

One example of an imaging system 300 is a CT system. A CT systemtypically includes a scanner which employs x-rays to create an imageutilizing the principle of attenuation. Attenuation represents a measureof the gradual loss in intensity of a flux, such as an x-ray, as itpasses through a medium, such as the tissue, bone and other materials ofthe body. CT systems generally include an x-ray source, typically anx-ray tube or tubes, and one or more x-ray sensors located opposite thex-ray source for capturing the attenuated x-rays after they pass throughthe body, including body structures that may be filled with acontrasting agent.

With respect to x-ray imaging techniques using iodine-based contrastagents, the attenuation and absorption of x-ray photons passing throughbody structures filled with iodinated contrast material increases as thevoltage applied to the x-ray source (e.g., x-ray tubes) decreases. Theincrease in attenuation is believed to be due to the dominance ofphoto-electric absorption at the lower x-ray excitation energies,especially as one approaches the K-Shell absorption peak of iodine. Thefollowing table (Table 1) reflects an art-recognized relationshipbetween x-ray tube voltage and the attenuation to contrast concentrationratio (aka, k-factor). (See Takanami, et al. 2008).

TABLE 1 Tube Voltage to K-Factor Relationship Tube Voltage (kV_(p))K-Factor (HU/(mgI · mL⁻¹)) 80 41 100 31 120 25 140 21

Because the attenuation to contrast concentration ratio varies based onthe voltage being applied to the x-ray tube, all else being equal, twoscans carried out using the same contrast concentration at differentx-ray tube voltages will produce different images. In particular, in theresulting imagery created by a CT system, an increased attenuationcreates a brighter opacification and greater image contrast between thecontrast-filled structures and the surrounding tissue. Because theopacification can increase as the tube voltage decreases, the volume ofcontrast needed to achieve sufficient contrast opacification in aterritory of interest can be reduced by using lower tube voltages.Similarly, because the opacification can decrease as the tube voltageincreases, a greater volume of contrast may be needed to achievesufficient contrast opacification and adequate imaging where higher tubevoltages are being used during the scanning procedure.

The present disclosure provides methods, systems, and algorithms forgenerating phase parameters predetermined as being effective for thetype of imaging procedure being performed that are based, at least inpart, on the tube voltage that will be applied during the imagingprocedure. Tailoring the phase parameters to account for tube voltagehas been found to not only lead to contrast savings, but also help toavoid less than ideal enhancement outcomes for higher tube voltageswhere the HU/(mgI.mL⁻¹) ratio is smaller. Such phase parameters can beestablished in a variety of ways, including through the collection ofpatient data over time (by, for example, employing artificialintelligence techniques, statistical means, adaptive learningmethodologies, etc.), through mathematical modeling, through themodification of baseline or known protocols to account for variations inthe tube voltage values, or otherwise.

In certain non-limiting embodiments, injection phase parameters asdescribed above are populated within a phase programming mechanism, orparameter generator, which may be a computer having software installedthereon for implementing the methods described herein, based on one ormore parameters of interest including, but not limited to, contrastagent concentration (for example, iodine concentration in the case of aCT procedure), a patient parameter (for example, body weight, height,gender, age, cardiac output, etc.) the type of scan being performed, thetype of catheter inserted into the patient for intravascular access, andthe voltage being applied when performing the imaging scan (for example,the voltage being applied to one or more x-ray tubes during a CT scan).The parameter generator is typically in communicative connection with atleast one of the imaging system 300 and the injector system 100. Theparameter generator can also include a processor (for example, a digitalmicroprocessor as known in the art) in operative connection with amemory. In some non-limiting embodiments, the parameter generator can beintegrated into the imaging system 300 and/or the injection system 100.

The phase programming mechanism can, for example, allow the operator tocontrol the injection system by entering a “protocol wizard orgeneration mode,” “helper mode”, or “operator assist mode.” Once theoperator chooses to enter the operator assist mode, the operator can bepresented with a graphical user interface that provides a mechanism ormode for entering the information used in populating the phaseparameters. In the operator assist mode, the protocol parameters areautomatically populated, generally in response to information input bythe operator through the graphical user interface and received at theparameter generator. The graphical user interface can present theoperator with a series of choices, such as questions about theprocedure, about the patient, or both, the answers to which can assistthe software associated with the phase programming mechanism indetermining the appropriate injection protocol and phase parameters.

For instance, one embodiment of a graphical user interface from whichthe operator is prompted to choose a region of interest for the image,and which follows the work flow described herein, is depicted in FIG. 2.The operator can, for example, choose a region of interest byhighlighting, for example, using a touch screen or a mouse controlledcursor, a region of interest on an illustration of the body set forth onthe user interface or can choose a region of interest from a menu suchas a pull down menu. Hierarchical groupings of regions of interest canbe provided.

Upon choosing the region to be imaged, the operator may be prompted toselect from among different available preset protocols, each of whichmay have preset parameters associated therewith, such as the contrastconcentration, whether a test injection or transit bolus are used, themaximum flow rate, the limitation on pressure, the injection duration,scan duration, etc., as shown in FIG. 2 and referred to therein as the“Details” of the protocol selected. The “Details” shown in FIG. 2 areexemplary only, and are not intended to be limiting. Preset protocolparameters may be stored in memory on the system, such as in memoryassociated with one or more of the above-described components of thesystem or in a database accessible over a network, and recalled when aparticular protocol is selected. These preset values may have beenentered into the system memory by an operator or someone associatedtherewith to reflect an operator's preferences for a particularprotocol. These values may also have been pre-loaded into the systemduring programming, and may reflect values that are commonly used in theindustry. Preset parameters such as “max flow rate” and “pressure limit”may be parameters that are set out of safety concerns for the patient.Others may be set as a function of the capabilities of the particularinjector or scanner hardware of the system. In some embodiments, thepreset values can be overridden, such as through direct entry of newvalues by an operator or through generation of a protocol requiringparameters inconsistent with the preset values. In the event that thepreset values are inconsistent with a generated protocol, the operatormay be prompted that such an event has occurred and given an opportunityto adjust and/or authorize the generated protocol.

Once a protocol is selected, the operator can then be prompted to entervalues for other variables (for example, patient physiological variablessuch as the patient's weight, height, gender, etc., or procedurevariables such as contrast concentration, tube voltage, scan duration,etc., though it should be understood that the general order in which theoperator is prompted for information or in which the operator entersinformation is not intended to be limiting. FIG. 3 shows an exemplarygraphical user interface wherein the variables “Patient Weight,”“Concentration” and “Tube Voltage” are selected or entered. An exampleof an embodiment or implementation of this is to provide a keypad on thegraphical user interface into which the operator enters the patient'sweight in pounds or kilograms. In another embodiment, the operatorchooses a weight range from among low, mid and high ranges. Similarly,the tube voltage can be entered using a keypad or selected from amongseveral preset values. Such variables can also be measured by one ormore sensing devices associated with the system and/or readelectronically or digitally from patient records as may be kept in ahospital database accessible over a network. For example, the system canbe configured to automatically populate the patient weight based onpatient records or automatically populate the tube voltage based on thecapabilities or current setting of the scanner of the associated imagingsystem. One or more of these variables may also be automaticallypopulated based on one or more criteria selected in a previous step,such as the preset protocol selected in FIG. 2. The automaticallypopulated value can then serve as the default unless and until changesare made thereto. The operator may also be queried if the operatorwishes to perform a test injection or timing injection.

The location of the graphical user interface within the system is notintended to be limiting. In addition to an interface on the injectorsystem, choices can also or alternatively be made on a graphical userinterface on the imaging system or scanner and/or from a database on theimaging system or scanner. In the case that the choices are made via aninterface or database resident on the scanner, the data can then betransmitted to the injector. Moreover, the interface can exist solely onthe scanner/imaging system. In this case, the final protocol can betransmitted to the injection system. Likewise, the interface or databasecan exist on a machine or system separate from the injector and thescanner. Data, for example, protocols can be transmitted from thatsystem to the injector. A communication interface that may be usedherein is disclosed in U.S. Pat. No. 6,970,735, the contents of which isincorporated herein by reference. One or more imaging systems can alsobe connected by way of a network with a central control location whereone or more computer interfaces can exist to display and/or allow forcontrol of the networked imaging systems. For example, multiple imagingsystems can be connected to a common computer or set of computerslocated in a control center, wherein an operator can monitor and adjustthe protocols being used on one or more of the imaging systems. Aradiologist wishing to specify the particular injection protocol to beused in a particular instance can take advantage of such a network toadjust the protocol from such an interface.

Based upon the selections made, the software implementing the presentinvention computes an injection protocol, including parameters such asthe flow rates and volumes for the phases, including the test injection,if any, for the operator's review. One such example of a graphical userinterface displaying an injection protocol for the operator's review isshown in FIG. 4.

In certain non-limiting embodiments, computation of the parameters ofthe injection protocol is done using a variable weight factor (mgIodine/Body weight kg) which is used to determine the dose, or totalvolume, of iodine for the patient for a particular tube voltage or rangethereof. In general, there is a linear relation between the plasmaconcentration of iodine and the enhancement (or CT Number) in HounsfieldUnits in a blood vessel. Weight is easily obtained before the patient isscanned and serves as a practical means of computing the preload volumeof contrast. The requirement to compute a preload volume can beeliminated through use of a continuous flow system using bulk containersof, for example, contrast and a flushing fluid or diluent (for example,saline) as described, for example, in U.S. Pat. Nos. 6,901,283,6,731,971, 6,442,418, 6,306,117, 6,149,627, 5,885,216, 5,843,037, and5,806,519, U.S. Patent Application Publication No. 2006/0211989 (U.S.patent application Ser. No. 11/072,999), and International PatentApplication Publication No. WO/2006/096388 (PCT International PatentApplication No. PCT/US2006/007030), the contents of which areincorporated herein by reference.

In several embodiments, the process software discretizes the weightranges of subjects in, for example, 7 ranges (for example, <40 kg, 40-59kg, 60-74 kg, 75-94 kg, 95-109 kg, 110-125 kg, >125 kg) and the tubevoltage in, for example, 4 values (80 kV_(p), 100 kV_(p), 120 kV_(p) and140 kV_(p)) for each weight range. Weight factors are associated witheach weight range/tube voltage combination. Exemplary weight factors,which depend upon and vary with patient weights and tube voltages, aredisplayed in Table 2 below.

TABLE 2 Exemplary Weight Factors (gI/kg) Weight Bin Weight Range (kg)Weight Range (lbs) 120 kV_(p) 1 <40 <88 0.5 2 40-59  88-131 0.46 3 60-74132-163 0.38 4 75-94 164-208 0.34 5  95-109 209-241 0.33 6 110-125242-276 0.31 7 >125  >276  0.3

The weight factors displayed in Table 2 were derived by applying amulti-objective optimization routine (Gembicki's weighted goalattainment method (Gembicki, F. W., “Vector Optimization for Controlwith Performance and Parameter Sensitivity Indices,” Case WesternReserve University (1974)) to simulated patients representing each ofthe weight ranges. This process is outlined in United States PatentApplication Publication Number 2010/0113887, assigned to the assignee ofthe present application, the entire contents of which are incorporatedby reference.

A similar multi-objective optimization was run to determine the weightfactor values for the same set of discretized weight ranges for tubevoltages of 80, 100 and 140 kV_(p). For each, a goal was set to attainan enhancement value of at least 325 HU in the right heart while keepingthe contrast volumes and flow rates as low as possible. The weightfactor values were calculated so as to provide the highest probabilityof meeting that goal. Other parameters were also considered indetermining the weight factors. For example, the optimal value of theweight factor generally increases as the scan duration increases. Thisis primarily because more contrast is needed to ensure the enhancementtarget is met in the entire scan window. Moreover, longer scan durationstypically imply lower flow rates, which can decrease enhancement andthus require additional contrast volume to compensate. However, theweight factors calculated can accommodate all scan duration values.

For each weight bin, the weight, height, age and gender were randomlygenerated for 50 simulated patients. The contrast dosing protocolparameters were varied during the simulation as follows:

Contrast Concentration: 320 and 370 mgI/mL

Scan Duration: 4, 10, 16 and 20 seconds

Minimum Injection Duration: 12 seconds

Max Flow Rate: 7 mL/s

Syringe Capacity: 194 mL

Dual Flow: ON and OFF

The right heart compartment enhancement was calculated as the averageenhancement during the scan window. A test bolus of 20 mL contrast, 40mL saline was used to determine the appropriate timing for the scanwindow. The minimum injection duration was not varied because it isusually set at 12 seconds when performing an injection for cardiacimaging. It is not generally necessary to vary the minimum injectionduration value as long as the scan duration values are chosen so as tosimulate all possible states of volume and flow rate adjustment duringprotocol generation.

For each of the simulated patients, all possible permutations of theabove parameters were simulated according to the PK model described byBae. K. T. Bae, J. P. Heiken, and J. A. Brink, “Aortic and hepaticcontrast medium enhancement at CT. Part I. Prediction with a computermodel,” Radiology, vol. 207, pp. 647-55 (1998); K. T. Bae, “Peakcontrast enhancement in CT and MR angiography: when does it occur andwhy? Pharmacokinetic study in a porcine model,” Radiology, vol. 227, pp.809-16 (2003); K. T. Bae et al., “Multiphasic Injection. Method forUniform Prolonged Vascular Enhancement at CT Angiography:Pharmacokinetic Analysis and Experimental Porcine Method,” Radiology,vol. 216, pp. 872-880 (2000); U.S. Pat. Nos. 5,583,902, 5,687,208,6,055,985, 6,470,889 and 6,635,030.

In choosing the best possible weight factor values, a set of enhancementcriteria were defined for each application. For pulmonary angiography,for example, the set goal was to achieve at least 325 HU of enhancementwhile using the least possible contrast and the lowest flow rate. A costfunction was constructed according to the following equation:Cost=0.7×|E _(RH)−325|+0.2×(R−5)+0.1×V _(cD)  (1)

R: flow rate (mL/s)

V_(cD): contrast diagnostic volume (mL)

E_(RH): Mean enhancement in right heart during scan window (HU)

In addition, it was considered desirable to restrict the number of caseswhere the right heart enhancement fell below 275 HU. Thus, for eachweight bin, the statistical distribution of weight factor values for allcases meeting a cost function target of 47.5, which was an arbitrarilyselected cost function target based on what was understood to be anacceptable value, was compared to the distribution of weight factorvalues for which the enhancement in the right heart was less than 275 HUand another distribution for cases not meeting the cost function targetwhere the flow rate exceeded 6 mL/s.

The histograms of each distribution were computed, and the point wherethe maximum positive difference between the high and low enhancementdistributions was observed was considered to be the best possible weightfactor value as it represents the value where the enhancement criteriawill be met most of the time and where the enhancement in the rightheart will only fall below 300 HU in a very limited number of cases.FIG. 5 shows an example of the histogram distribution for a tube voltageof 100 kV_(p) and a weight bin of 40-59 kg.

From the histogram shown in FIG. 5, a weight factor of 0.39 gI/kg wasconsidered optimal for the subject weight range/tube voltagecombination. Less than 1% of low enhancement cases occurred at thisvalue according to the simulation. A cumulative distribution functionwould show that no cases of low enhancement or high flow rate occur forweight factors greater than or equal to 0.4 gI/kg. Thus, choosing thepoint of largest positive difference also ensures there is very littleoverlap between the two distribution curves.

The simulations described above were used to determine if patient orinjection protocol parameters are likely to influence the enhancementoutcomes, or, in other words, to determine whether it is more likely toachieve the specified enhancement target for either a given type ofpatient or a specific injection protocol. To analyze the effect ofpatient age, for example, the average age of simulated patients who metthe 325 HU target was compared to the average age of the entiresimulated patient population. This was done for each value of the tubevoltage and across all weight bins. The results are shown in Table 3,below.

TABLE 3 Influence of Patient Age Average Age Age Std. Range Category(yrs) Dev. (yrs) p-value All patients 42.7 20.15 10-86 — Target Met at80 kV_(p) 47.36 19.36 10-86 9 × 10⁻⁴ Target Met at 100 kV_(p) 47.3619.36 10-86 9 × 10⁻⁴ Target Met at 120 kV_(p) 48.1 19.21 10-86 TargetMet at 140 kV_(p) 49.9 19.52 10-86 1.55 × 10⁻⁶  

The results of Table 3 show that the average age of patients in caseswhere the enhancement target is met is statistically significantlydifferent from the average age of the overall patient population,demonstrating a slight tilt towards older patients. A likely explanationfor this is that, generally speaking, older patients tend to exhibitlower cardiac output values, which leads to higher enhancement peaks.

The height of the simulated patients was also evaluated in a similarway, and the results of this evaluation are shown in Table 4, below.

TABLE 4 Influence of Patient Height Average Height Height Std. RangeCategory (in) Dev. (in) p-value All patients 67.52 7 48-79 — Target Metat 80 kV_(p) 65.77 7.6 48-79 0 Target Met at 100 kV_(p) 67.56 7.64 48-798.59 × 10⁻⁷ Target Met at 120 kV_(p) 66.4 7.1 48-79 0 Target Met at 140kV_(p) 66.41 6.9 48-79 0

From the results shown in Table 4, it is evident that the differences inheight between the groups where the enhancement target is met and thegeneral patient population are not significant. The difference achievesstatistical significance, but in physical terms has no practicalmeaning.

The influence of scan duration was also measured, which was observed bycalculating for each tube voltage value the percentage of scans whichsuccessfully met the target obtained for each of the four scan durationvalues. The results of this evaluation are shown in Table 5.

TABLE 5 Percentage of success for different scan durations Tube Voltage4 sec 10 sec 16 sec 20 sec  80 kV_(p) 24% 23% 25% 28% 100 kV_(p) 32% 22%23% 23% 120 kV_(p) 36% 25% 20% 19% 140 kV_(p) 40% 27% 17% 16%

In Table 5, the proportion of successful cases occurring for scandurations of 4 and 10 seconds tends to increase as the tube voltageincreases while it decreases for scan durations of 16 and 20 seconds.This is likely, at least in part, because for longer scan durations, theaverage enhancement is lower due to both a longer scan window and aslower contrast injection rate. As the tube voltage increases, theamount of contrast required to attain the enhancement target increasesas well. This can lead to instances where the amount of contrastcalculated by the protocol exceeds the syringe capacity, leading to alower than expected enhancement plateau in the scan window. When thisoccurs, the shorter scan duration windows are more likely to meet theenhancement target since the scan will only occur during the period ofhighest enhancement.

The influence of contrast concentration and gender were also evaluated,and the results of this evaluation are shown in Tables 6 and 7, below.

TABLE 6 Percentage of success for contrast concentration Tube Voltage320 mgI/mL 370 mgI/mL  80 kV_(p) 48% 52% 100 kV_(p) 55% 45% 120 kV_(p)50% 50% 140 kV_(p) 47% 53%

TABLE 7 Percentage of success for gender Tube Voltage Male Female  80kV_(p) 52% 48% 100 kV_(p) 51% 49% 120 kV_(p) 49% 51% 140 kV_(p) 45% 55%

From the data in Table 6, it does not appear that contrast concentrationhas a particular influence on the incidence of success as both testedcontrast concentrations led to similar percentages of successfuloutcomes. Similarly, from Table 7, it does not appear that gender hasany particular influence on successfully achieving enhancement targets.

The above simulations were used to develop the weight factors of Table8, below.

TABLE 8 Exemplary Weight Factors (gI/kg) Weight Weight Weight RangeRange Bin (kg) (lbs) 80 kV_(p) 100 kV_(p) 120 kV_(p) 140 kV_(p) 1  <40 <88 0.36 0.44 0.5 0.59 2 40-59  88-131 0.33 0.39 0.46 0.51 3 60-74132-163 0.28 0.33 0.38 0.44 4 75-94 164-208 0.26 0.31 0.34 0.4 5  95-109209-241 0.24 0.29 0.33 0.39 6 110-125 242-276 0.23 0.27 0.31 0.377 >125 >276 0.23 0.27 0.3 0.35

Additionally, the weight factors in Table 8 were verified to ensure thatthey do not yield unrealistic injection protocols. To do so, statisticalanalysis of the flow rate and contrast volume usage was performed toverify that injection protocols generated according to the procedureoutlined in U.S. Patent Application Publication No. 2010/0113887 usingthese weight factors were feasible. The results of this analysis areshown in FIGS. 6-8 and described below.

FIG. 6 shows that contrast volumes calculated with the weight factorvalues of Table 8 will not yield unrealistic protocols in terms of totalvolume of contrast delivered. As shown, the average volume increasedwith tube voltage and with weight bin, as expected. The smallest volumeof contrast calculated at 80 kV_(p) was 29.2 mL, while the largestvolume of contrast calculated at 140 kV_(p) was 161 mL. This is therange of volumes calculated by the protocol algorithms of U.S. PatentApplication Publication No. 2010/0113887 using the weight factors ofTable 8.

In FIG. 7, the flow rates calculated by the algorithm using the weightfactors of Table 8 also increased with tube voltage and weight bin. Thevalues calculated are all realistic and are all capable of being used ininjection protocols in a clinical setting. The slowest rate used in thesampling at 80 kV_(p) was 2 mL/s and the fastest rate used at 140 kV_(p)was 7 mL/s, due to flow rate limitations.

The mean right heart enhancement across the scan window was alsocalculated using the weight factors of Table 8 and the results aredisplayed in FIG. 8. For most weight bins, the enhancement target of 325HU was easily met when the tube voltage was set to either 80 kV_(p) or100 kV_(p). For 120 kV_(p) and 140 kV_(p) settings, the enhancementtarget was not met as often, in part because for these values, syringecapacity can be a limiting factor and cause an injection protocol to gettruncated. Moreover, at 120 kV_(p), the weight factors were set at orbelow the original weight factor values in an effort to limit the flowrates and volumes for pulmonary angiography applications.

Clinical testing of the weight factors of Table 8 was also conductedusing patient data from clinical trials at UPMC and Muenster. In thetesting, there were 105 patients, whose summary statistics are presentedin Table 9 below.

TABLE 9 Test Set Data Statistics Mean Standard Deviation Range Weight(lbs) 180.12 44.9  90-450 Height (inches) 68.3 3.86 59-78 Age (years)50.8 18.07 19-89

The sampling included 63 male patients and 42 female patients. FIGS. 9,10, and 11 represent the weight, height and age distribution of thesampling, respectively.

The simulation described above was run on this patient data using theweight factors of Table 8. For each patient weight, an injectionprotocol was calculated according to the protocol calculation processoutlined in U.S. Patent Application Publication No. 2010/0113887 foreach tube voltage and the average flow rate of each of the injectionprotocols was plotted against patient weights for each tube voltagevalue. The results are shown in FIG. 12. In these results, the flowrates increased as the tube voltage value increased, but the averagevalue of the flow rates stayed inferior to 6 mL/s, even for the highesttube voltage setting. The flow rates obtained for the calculatedinjection protocols were thus within the expected range.

Similarly, the total contrast volume used in the injection protocol,including in the diagnostic phase and the dual flow phase, was alsocalculated for each patient and plotted against weight, the results ofwhich are shown in FIG. 13. In FIG. 13, the average volume stayed under100 mL for all injection protocols. There were, however, cases where thevolume exceeded 100 mL, particularly for the heavier patients.

FIG. 14 reflects the effect of scan duration on the right heartenhancement value in the patient sampling. FIG. 14 shows that theenhancement value is lower for 16 and 20 second scan durations than for4 and 10 second scan durations. This is believed to be due, at least inpart, to the fact that the enhancement value was calculated as theaverage enhancement value in the scan window, thus causing longer scanwindows to have lower average enhancement values. Moreover, as shown inFIG. 15, shorter scan durations typically result in higher flow rates,further contributing to an increase in the enhancement value. However,if the scan duration is shorter than the minimum injection durationtested of 4 seconds, the diagnostic phase contrast volume is reduced,which explains why the enhancement tends to be lower for 4 second scandurations than for 10 second scan durations. The enhancement also tendedto dip below 300 HU for scan durations above 16 seconds in FIG. 14.

FIG. 16 shows the effect of the minimum injection duration on the meanenhancement value. In particular, for the patient sampling plotted inFIG. 16, the average enhancement in the right heart falls below 300 HUfor tube voltage values of 120 kV_(p) and 140 kV_(p), but remains abovethis threshold for the lower tube voltage values, regardless of the scanduration programmed.

Using the weight factors, injection protocols for a patient can bedetermined by the system according to a weight-based algorithm. One suchembodiment of a weight-based algorithm for determining a volume of apharmaceutical fluid, such as contrast, that is to be injected during aninjection phase is represented by the following equation:V ₁=patient weight*X*Y  (2)

V₁: volume of pharmaceutical fluid to be delivered in the phase;

X: weight factor;

Y: contrast concentration in pharmaceutical fluid

Once the total volume to be delivered during a particular phase isknown, the system can determine the appropriate flow rate for aparticular phase according to the formula:Flow Rate=V ₁/injection duration  (3)

The injection duration can be determined in a variety of ways. Forexample, the injection duration can be determined by the system basedupon one or more criteria concerning the imaging procedure (e.g., theregion of the body to be imaged) and/or the patient (e.g. patientweight), it can be a value that is inputted directly by the operator, orit can represent a preset parameter, as described above.

Parameters of additional phases can be similarly determined. Forexample, the system can determine parameters for a first phase in whichonly the pharmaceutical fluid is to be delivered and a second, dilutedphase in which both the pharmaceutical fluid and a diluent, such assaline, are to be delivered.

The implementation software can be programmed to generate parameters ofthe injection protocol based on the above algorithms and weight factors,which are based, in part, on the x-ray tube voltage. Once generated, theparameters can be populated in the graphical user interface for operatorreview. As described previously, FIG. 4 represents an embodiment of agraphical user interface capable of presenting an injection protocol tothe operator for review. In different embodiments, the weight factorscan be determined by the system through an algorithmic approach wherebythe weight factors are calculated using information about patientweight, tube voltage, etc., such as is described above. The weightfactors can alternatively, or additionally, preexist in memory, such asin a lookup table data file loaded onto the system or accessible by thesystem across a network, allowing the weight factors to be recalled whenneeded. Table 8, for example, illustrates exemplary informationconcerning the weight factors that could be made available in a lookuptable.

In other non-limiting embodiments, determination of appropriateinjection protocol parameters can be accomplished by modifying oradjusting protocol parameters of a baseline injection protocol using atube voltage modification factor to account for differences between thevoltage being applied to an x-ray tube during a particular scan (orphase thereof) and the tube voltage that was used or assumed indetermining the parameters of the baseline protocol.

For purposes of this disclosure, baseline injection protocols includeprotocols that have been established in the clinical literature,established through the collection of patient data over time by, forexample, employing artificial intelligence techniques, statisticalmeans, adaptive learning methodologies, etc., or established throughmathematical modeling. These protocols may depend on, for example,contrast agent concentration, for example, iodine concentration in thecase of a CT procedure, a patient parameter, for example, body weight,height, gender, age, cardiac output, etc., the type of scan beingperformed, the type of catheter inserted into the patient forintravascular access, and/or other patient specific data. In somenon-limiting examples, baseline protocols have been, or can be,generated using a weight factor similar to the generation of protocolsusing weight factors discussed above. Such protocols, as well as methodsand systems for generating such protocols, are described in PCTInternational Patent Application No. PCT/US05/41913, entitled MODELINGOF PHARMACEUTICAL PROPAGATION, filed Nov. 16, 2005, claiming the benefitof U.S. Provisional Patent Application Ser. No. 60/628,201, assigned tothe assignee of the present invention, and PCT International PatentApplication No. PCT/US07/26194, entitled PATIENT-BASED PARAMETERGENERATION SYSTEMS FOR MEDICAL INJECTION PROCEDURES, filed Dec. 21,2007, claiming the benefit of U.S. Provisional Patent Application Ser.Nos. 60/877,779 and 60/976,002, assigned to the assignee of the presentinvention, the disclosures of which are incorporated herein byreference.

Baseline injection protocols for use herein may be stored in memory onthe system, made accessible to the system across a network, ordetermined by the system in response to one or more inputted values. Forexample, a series of baseline injection protocols, each known to provideoptimal dosing parameters for a certain combination of scan region, bodyweight, contrast concentration, etc. at a particular tube voltage may bestored in memory. The system can then recall from memory informationabout the appropriate baseline protocol for use in generating aninjection protocol once sufficient information about the to-be-generatedinjection protocol is known. For example, when an operator selects ascan region/body weight/contrast concentration combination for a newinjection procedure, the system can recall a baseline protocol generatedfor the same, or a similar, combination of scan region/bodyweight/contrast concentration. Alternatively, the system may containsoftware which can compute baseline injection protocols based on one ormore patient-specific or procedure-specific criteria inputted by theoperator, including the values discussed above (e.g., patient-specificand procedure-specific parameters).

Baseline injection protocols generally reflect optimal contrast dosingparameters at a particular tube voltage, which is referred to herein asthe baseline tube voltage. The most common baseline tube voltage is 120kV_(p). The baseline tube voltage associated with a baseline injectionprotocol can be stored along with other information about the baselineinjection protocol, though in some non-limiting embodiments the operatormay be prompted to enter the baseline tube voltage for a particularbaseline injection protocol or the baseline tube voltage may be assumedto be 120 kV_(p). Because of the relationship between tube voltage andattenuation, a baseline injection protocol may not provide optimalcontrast dosing parameters if a tube voltage other than the baselinetube voltage is being applied when using that protocol. Accordingly, thebaseline protocol parameters can be modified or adjusted in order toachieve more optimal contrast dosing at the new tube voltage value.Since the modified parameters are not readily known to the operator ofthe injector, the parameter generation system described herein eases thetask of an operator by providing tube voltage modification factors thatshould be used in conjunction with a baseline injection protocol todetermine more optimum injection parameters for the tube voltage ofinterest.

In several non-limiting embodiments, applying a tube voltagemodification factor to one or more of the parameters of a baselineinjection protocol may be used to create a new injection protocoltailored for the particular tube voltage to be used in the scan, such asby adjusting or modifying the parameters of the baseline protocol.

In one non-limiting embodiment, the tube voltage modification factorsare determined from an analysis of the relationship between theattenuation to contrast concentration ratios (k-factor) and tubevoltage. The relationship between the k-factor and tube voltage can beestablished through a review of the clinical literature, and an artrecognized relationship is shown in Table 1 above. Alternatively, oradditionally, the relationship between the k-factor and the tube voltagecan be determined by performing a calibration exercise at the scanner.

One such calibration exercise involves preparing a number of vials, eachcontaining a mix of a known iodine concentration, typically in mgI/mL.The vials are then scanned at different tube voltages, such as at 80,100, 120, and 140 kV_(p), and the attenuation value for each vial ateach tube voltage is recorded. The tube voltages tested should at leastinclude the baseline tube voltage used in determining the baselineprotocol, which is typically 120 kV_(p), as well as any other tubevoltages that may be used with the scanner, the reason for which willbecome apparent below. For each of the tube voltages tested, the vialconcentrations are plotted against the recorded attenuation values and abest-fit line is prepared for each tube voltage. For each tube voltage,the slope of the best-fit line represents the respective k-factor forthat particular tube voltage, in units of HU/mgI/mL. Typical k-factorvalues determined according to this calibration exercise shouldgenerally correspond to those art recognized values reported in Table 1.

The tube voltage modification factors for different tube voltages can bedetermined based on the k-factors and information about the baselinetube voltage by calculating the relative increase or decrease in thek-factor between a particular tube voltage and the baseline tubevoltage. For example, if the baseline tube voltage has a k-factor of 25HU/mgI/mL, the tube voltage modification factor corresponding to a tubevoltage having a k-factor of 41 HU/mgI/mL would be calculated as(25-41)/41, or −39%.

Table 10 below illustrates tube voltage modification factors fordifferent tube voltages assuming the baseline tube voltage is 120kV_(p), using the k-factors from Table 1.

TABLE 10 Sample Tube Voltage Modification Factor Calculation TubeVoltage (kV_(p)) k-Factor (HU/mgI/ml) Modification Factor 80 41 (25 −41)/41 = −39% 100 31 (25 − 31)/31 = −19% 120 25 (25 − 25)/25 = 0% 140 21(25 − 21)/21 = +19%

Additional adjustment of the calculated tube voltage modificationfactors may be appropriate at the operator's discretion, as otheraspects of the image, noise in particular, change with tube voltagemodifications. Therefore, an operator may prefer that instead of a 39%decrease at 80 kV_(p), for example, only a 30% decrease be used. Whilethe default computed values are suggested by the software based on thecalibration experiment results, the operator would be able to modify thesuggested values at his or her preference.

Once the tube voltage modification factors are known, the operator maydecide which parameters of the baseline injection protocol should beadjusted based on the modification factors. For example, the operatormay decide that both the total volume and flow rate parameters should beadjusted based on the tube voltage modification factor in order tomaintain a constant injection duration, or only the total volume may bedecreased in order to maintain a constant flow rate and decrease theinjection duration. Typically, if the flow rate of contrast is modified,the flow rates of any saline phases are adjusted by the same amount tomaintain consistency between the diagnostic contrast phases, the salinepatency checks, and the saline flushes. Alternatively, the software canbe set to automatically select one or more parameters of the baselineinjection protocol to adjust according to the tube voltage modificationfactor, typically the volume and flow rate.

The parameter generator must also know or be able to identify the tubevoltage to be applied as part of the new injection procedure in order todetermine the appropriate tube voltage modification factor to apply. Forexample, the value of the tube voltage can be inputted by the operatordirectly to the parameter generator or the parameter generator canreceive information about the tube voltage from the scanner or anothercomponent of the system, wherein the tube voltage is known to thecomponent because of a particular setting or capability of the componentor because an operator has input the tube voltage value to thecomponent. Once known, an injection protocol can be generated byapplying the tube voltage modification factor to the baseline protocolparameters. For example, in the case of modifying the volume and flowrate of the baseline protocol, generation of new volume and flow rateparameters involves increasing or decreasing the volume and flow rateparameters of the baseline protocol by the tube voltage modificationfactor. Generation of the injection protocols can be accomplished by thesoftware of the system by recalling from memory and/or generating abaseline protocol, determining a tube voltage modification factor basedon the details of the baseline protocol selected, including the baselinetube voltage and the intended tube voltage to be applied, and adjustingthe baseline protocol parameters by the tube voltage modificationfactor.

Adjustment of the protocol parameters using the tube voltagemodification factor allows for a baseline protocol to be modified inorder to maintain similar enhancement characteristics despite a changein the tube voltage. For example, if a given volume and flow rateprovide 300 HU of enhancement in a given region of interest scanned at120 kV_(p), the iodine concentration in that region can be calculatedfrom the k-factor in Table 1 to be 12 mgI/mL (300 HU÷25 HU/mgI/ml).Using the same volume and flow rate (and thus assuming the same iodineconcentration in that region) to scan the same region of interest at 100kV_(p) would be expected to provide 372 HU of enhancement using thek-factor in Table 1 (31 HU/mgI/mL*12 mgI/mL). To maintain the 300 HU at100 kV_(p), the volume and/or flow rate can be decreased by the tubevoltage modification factor of 19% to obtain an iodine concentration of9.7 mgI/mL.

Similar to the embodiments described above, an operator can be presentedwith a graphical user interface that provides a mechanism or mode forentering the information necessary for populating the phase parametersbased on a tube voltage modification factor.

For instance, one embodiment of a graphical user interface from whichthe operator chooses a region of the body of interest, and which followsa workflow described with reference to FIGS. 17, 19, 21 and 23, isdepicted in FIG. 17. The operator can, for example, choose a region ofinterest by highlighting, for example, using a touch screen or a mousecontrolled cursor, a region of interest on an illustration of the bodyset forth on the user interface or can choose a region of interest froma menu such as a pull down menu. Hierarchical groupings of regions ofinterest can be provided. FIG. 18 depicts another embodiment of agraphical user interface from which an operator can choose a region ofinterest, and an alternative work flow is described herein withreference to FIGS. 18, 20, 22 and 24.

Upon choosing the region of the body to be imaged, the operator may beprompted to select from among different available baseline protocols,each of which may have preset parameters associated therewith. Forexample, FIG. 17 illustrates a user interface presenting a singleprotocol option, labeled as “Head Protocol 1,” which, upon selection,can display a default flow rate and volume for each phase, along withthe total diagnostic contrast volume and total diagnostic saline volume,as also shown in FIG. 17. FIG. 18 illustrates a user interfacepresenting multiple baseline protocols from among which the baselineprotocol can be selected. The selected baseline protocol may haveadditional parameters associated therewith, such as injection pressureor flow rate limits, iodine concentration, scan duration, whether a testbolus is performed, etc., which may or may not be displayed and whichmay or may not be capable of being adjusted. FIG. 18 represents anexample where additional details about the particular baseline protocolselected are displayed to the operator. An indicator may also beassociated with the preset protocol indicating that the particularprotocol can be adjusted based on a tube voltage modification rule, suchas through the use of tube voltage modification factors as discussedabove. The exemplary interfaces of FIG. 17 and FIG. 18 represent this bythe “kV_(p)” icon associated with the “Head Protocol 1” and the “Cardiacw/Bolus Tracking” protocols. Other available protocols may not have atube voltage modification option associated therewith, such as the “DrA's Cardiac” protocol in FIG. 18.

Following selection of the region to be imaged and the baselineprotocol, the operator can be prompted to enter values for the tubevoltage that will be used. FIG. 19 depicts an example of a graphicalinterface wherein the “Tube Voltage” can be selected or entered. In thisexample, the tube voltage can be selected from among several presetvalues, though the tube voltage can also be entered using a keypad orthe like. The tube voltage value may also be automatically populatedbased on the capabilities or setting of the associated scanner. FIG. 20depicts another example of an interface wherein “Tube Voltage” can beselected from among various choices. In the embodiment of FIG. 20,“Patient Weight” and “Concentration” are additional parameters availablefor selection by the operator. The particular parameters depicted inFIGS. 19 and 20 are not intended to be limiting, and other parametersare contemplated for selection by the operator consistent with thediscussion above.

Following selection of the tube voltage, baseline protocol and/or otherinputs such as patient weight and iodine concentration, theimplementation software of the parameter generator can determine theappropriate modification of the baseline protocol, such as through thedetermination of a tube voltage modification factor. The operator canthen be presented with an interface informing the operator of theparameters selected and the associated adjustment made as a result ofthe selected tube voltage value. An example of one such interface isshown in FIG. 21, which confirms to the operator that the tube voltagevalue of 100 kV_(p) has been selected and, under “Notice,” that theselected tube voltage value is associated with a 19% decrease in thevolume of contrast from the baseline contrast volume. FIG. 22 similarlydepicts an example of an interface which informs the operator of theselected patient weight, iodine concentration, and tube voltage valuesand that a 19% decrease in contrast volume is associated with theparticular tube voltage selected from the baseline value.

Based upon the selection of tube voltage made, the implementationsoftware computes an injection protocol using the tube voltagemodification factor. The protocol parameters such as the flow rates andvolumes for the phases (including the test injection, if any), can thenbe presented to the operator for his or her review. One such example ofan interface displaying a computed injection protocol is shown in FIG.23. Another such example is depicted in FIG. 24.

Once review of the computed protocols is complete, the operator caninitiate the injection process, which will be performed according to theparticulars of the generated protocol.

FIG. 25 depicts one example of the methodology associated with theembodiments involving tube voltage modification. The left hand side ofthe chart illustrates an example of this methodology applied to astandard protocol. Step 1 represents selection by the operator of astandard protocol, consistent with FIG. 17. Step 2 represents selectionof the tube voltage from the list of tube voltages illustrated in FIG.19. Step 3 depicts application of the modification factor to theparameters in accordance with the particular tube voltage selected instep 2. This step corresponds to that illustrated in connection with thegraphical user interface of FIG. 21. Step 4 represents the display ofthe modified protocol, as shown in FIG. 23. Similarly, steps 1-4 on theright hand side of the chart depict application of the tube voltagemodification to a preset protocol of the type that can be obtained usingone or more of the P3T® Technology products available from MEDRAD, INC.,a business of Bayer HealthCare. These steps follow the illustrations ofFIGS. 18, 20, 22 and 24, respectively.

FIG. 26 depicts an example of the methodology underlying the embodimentsin which the tube voltage parameter is integrated directly into thealgorithm(s) of the present invention. Step 2 illustrates entry of theparameters, such as the appropriate tube voltage value, into thealgorithms embodied in, for example, the P3T® Cardiac or P3T® PAproducts, for imaging of the vasculature of the heart and lungs,respectively. Embodying the adjusted dosing factors obtained from thismethod, the resulting protocol is generated in step 3 and then displayedin step 4.

FIG. 27 illustrates an example of the methodology underlying theembodiments in which the protocol calculations are performed with atleast some inputs obtained from the scanner. Step 1 shows that theinitial protocol may be selected from the scanner, with the scannerupdating in step 2 the entered input values inclusive of tube voltage.After the input values are read in step 3, the protocol calculator thendetermines the resulting protocol either by employing the rule-basedmodifications represented by steps 4a and 4b on the left hand side ofthe chart or the dosing factors represented by step 4 on the right handside. Steps 5 and 6 represent the actions of conveying the resultingprotocol to the scanner (e.g., for display) and also conveying it backto the injector, respectively.

The representative embodiments set forth above are discussed primarilyin the context of CT imaging. However, the devices, systems and methodsdescribed herein have wide applicability to the injection ofpharmaceuticals. For example, the systems, devices and methods discussedabove may be useful in connection with the injection of contrast mediafor tomographic imaging procedures other than CT.

In general, the embodiments of a parameter generation system describedabove determine the parameters of an initial protocol using informationavailable to the operator, including information about the tube voltageto be applied during the imaging procedure. The initial protocolprovides information on the volume of one or more fluids to be deliveredto, for example, enable preloading of one or more syringes. Theparameters of the generated protocol may be adjusted on the basis ofcharacterization of the cardiovascular system. The parameter generationsystems of this disclosure were described in connection with aninjection including an initial contrast only injection phase and asubsequent admixture phase. As will be understood by one skilled in theart, the present parameter generation system is applicable to theinjection of various pharmaceuticals, with or without injection ofdiluent of flushing fluids, via injection protocols that can includeone, two of more phases.

Although the present invention has been described in detail inconnection with the above embodiments and/or examples, it should beunderstood that such detail is illustrative and not restrictive, andthat those skilled in the art can make variations without departing fromthe invention. The scope of the invention is indicated by the followingclaims rather than by the foregoing description. All changes andvariations that come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

The invention claimed is:
 1. A patient imaging system, comprising animaging system and a parameter generator of the patient imaging systemto determine parameters of at least a first phase of an injectionprocedure, wherein the imaging system comprises a scanner comprising atleast one x-ray tube and wherein the parameter generator comprises aprocessor and is programmed to determine at least one of the parameterson the basis of a voltage to be applied to the at least one x-ray tubeduring an imaging procedure, wherein the parameter generator isprogrammed to determine at least one of a volume of a pharmaceuticalfluid to be injected during at least the first phase and a flow rate ofthe pharmaceutical fluid to be injected during at least the first phaseon the basis of the voltage to be applied to the at least one x-ray tubeduring the imaging procedure, wherein the parameter generator isprogrammed to determine the volume of the pharmaceutical fluid to beinjected during at least the first phase by adjusting a volume parameterof a baseline injection protocol, and wherein the patient imaging systemfurther comprises an injector system in operable communication with theparameter generator, and comprising at least one source of thepharmaceutical fluid, wherein the injector system injects thepharmaceutical fluid during at least the first phase according to thedetermination of the volume of the pharmaceutical fluid to be injectedduring at least the first phase.
 2. The patient imaging system of claim1, wherein data representing the baseline injection protocol exists in amemory of the patient imaging system or accessible to the patientimaging system.
 3. The patient imaging system of claim 1, wherein theparameter generator is programmed to determine the baseline injectionprotocol on the basis of one or more criteria inputted by an operator.4. The patient imaging system of claim 1, wherein the parametergenerator is programmed to determine the volume of the pharmaceuticalfluid to be injected during at least the first phase by applying a tubevoltage modification factor to the volume parameter of the baselineinjection protocol.
 5. The patient imaging system of claim 1, whereinthe parameter generator is programmed to determine the flow rate of thepharmaceutical fluid to be injected during at least the first phase byadjusting a flow rate parameter of a baseline injection protocol.
 6. Thepatient imaging system of claim 5, wherein data representing thebaseline injection protocol exists in a memory of the patient imagingsystem or accessible to the patient imaging system.
 7. The patientimaging system of claim 5, wherein the parameter generator is programmedto determine the baseline injection protocol on the basis of one or morecriteria inputted by an operator.
 8. The patient imaging system of claim5, wherein the parameter generator is programmed to determine the flowrate of the pharmaceutical fluid to be injected during at least thefirst phase by dividing the volume of the pharmaceutical fluid to beinjected during the first phase by an injection duration of the firstphase.
 9. A method of operating a system for controlling an injectorsystem for delivering a pharmaceutical fluid to a patient as part of animaging procedure, the injector system in operative connection with animaging system comprising a scanner comprising at least one x-ray tube,the steps of the method comprising: (a) determining, by a parametergenerator of the system, wherein the parameter generator comprises aprocessor, injection parameters of at least a first phase of aninjection procedure, wherein at least one of the injection parameters isdetermined on the basis of a voltage to be applied to the at least onex-ray tube during the imaging procedure; (b) controlling, by the system,the injector system at least in part on the basis of the determinedinjection parameters, wherein the parameter generator determines atleast one of a volume of a pharmaceutical fluid to be injected during atleast the first phase and a flow rate of the pharmaceutical fluid to beinjected during at least the first phase on the basis of the voltage tobe applied to the at least one x-ray tube during the imaging procedure,and wherein the parameter generator determines the volume of thepharmaceutical fluid to be injected during at least the first phase byadjusting a volume parameter of a baseline injection protocol; and (c)injecting, by the injector system, the pharmaceutical fluid during atleast the first phase according to the determination of the volume ofthe pharmaceutical fluid to be injected during at least the first phase.10. The method of claim 9, wherein data representing the baselineinjection protocol is recalled from a memory associated with oraccessible by at least one of the injector system, the imaging system,and the parameter generator.
 11. The method of claim 9, wherein thebaseline injection protocol is determined on the basis of one or morecriteria inputted by an operator.
 12. The method of claim 9, wherein thevolume of the pharmaceutical fluid to be injected during at least thefirst phase of the injection procedure is determined by applying a tubevoltage modification factor to the volume parameter of the baselineinjection protocol.
 13. The method of claim 9, wherein the flow rate ofthe pharmaceutical fluid to be injected during at least the first phaseis determined by adjusting a flow rate parameter of the baselineinjection protocol.
 14. The method of claim 13, wherein datarepresenting the baseline injection protocol is recalled from a memoryassociated with or accessible by at least one of the injector system,the imaging system, and the parameter generator.
 15. The method of claim13, wherein the baseline injection protocol is determined on the basisof one or more criteria inputted by an operator.
 16. The method of claim13, wherein the flow rate of the pharmaceutical fluid to be injectedduring at least the first phase is determined by dividing the volume ofthe pharmaceutical fluid to be injected during the first phase by aninjection duration of the first phase.
 17. The method of claim 9, themethod further comprising the step of populating the determinedinjection parameters on a graphical user interface associated with atleast one of the injector system and the imaging system.
 18. A method ofgenerating an injection protocol for use with an injector system inoperative connection with an imaging system comprising a scannercomprising at least one x-ray tube, the method comprising the steps of:(a) determining, by a parameter generator comprising a processor,injection parameters of at least a first phase of an injectionprocedure, wherein at least one of the injection parameters isdetermined on the basis of a voltage to be applied to the at least onex-ray tube during an imaging procedure, wherein the parameter generatordetermines at least one of a volume of a pharmaceutical fluid to beinjected during at least the first phase and a flow rate of thepharmaceutical fluid to be injected during at least the first phase onthe basis of the voltage to be applied to the at least one x-ray tubeduring the imaging procedure, and wherein the parameter generatordetermines the volume of the pharmaceutical fluid to be injected duringat least the first phase by adjusting a volume parameter of a baselineinjection protocol; and (b) injecting, by the injector system, thepharmaceutical fluid during at least the first phase according to thedetermination of the volume of the pharmaceutical fluid to be injectedduring at least the first phase.
 19. The method of claim 18, the methodfurther comprising the step of receiving, at the parameter generator,information identifying a region of the body to be scanned, wherein atleast one of the injection parameters is determined on the basis of theregion of the body to be scanned.
 20. The method of claim 18, furthercomprising the step of receiving, at the parameter generator,information about the weight of a patient, wherein at least one of theinjection parameters is determined on the basis of the weight of thepatient.
 21. An injection system for delivering a pharmaceutical fluidto a patient via an injection procedure performed in connection with animaging procedure, the imaging procedure being performed with an imagingsystem comprising a scanner having at least one x-ray tube, theinjection system comprising: a parameter generator comprising aprocessor, wherein the parameter generator is programmed for determiningparameters of at least a first phase of the injection procedure whereinat least one of the parameters is determined on the basis of a voltageto be applied to the at least one x-ray tube of the imaging systemduring the imaging procedure, wherein the parameter generator isprogrammed to determine at least one of a volume of the pharmaceuticalfluid to be injected during at least the first phase and a flow rate ofthe pharmaceutical fluid to be injected during at least the first phaseon the basis of the voltage to be applied to the at least one x-ray tubeduring the imaging procedure, and wherein the parameter generator isprogrammed to determine the volume of the pharmaceutical fluid to beinjected during at least the first phase by adjusting a volume parameterof a baseline injection protocol, such that the injection systemdelivers the pharmaceutical fluid to the patient during at least thefirst phase of the injection procedure according to the determination ofthe volume of the pharmaceutical fluid to be injected during at leastthe first phase.
 22. The injection system of claim 21, wherein datarepresenting the baseline injection protocol exists in a memory of theinjection system or accessible to the injection system.
 23. Theinjection system of claim 21, wherein the parameter generator isprogrammed to determine the baseline injection protocol on the basis ofone or more criteria inputted by an operator.
 24. The injection systemof claim 21, wherein the parameter generator is programmed to determinethe volume of the pharmaceutical fluid to be injected during at leastthe first phase by applying a tube voltage modification factor to thevolume parameter of the baseline injection protocol.
 25. The injectionsystem of claim 21, wherein the parameter generator is programmed todetermine the flow rate of the pharmaceutical fluid to be injectedduring at least the first phase by adjusting a flow rate parameter of abaseline injection protocol.
 26. The injection system of claim 25,wherein data representing the baseline injection protocol exists in amemory of the injection system or accessible to the injection system.27. The injection system of claim 25, wherein the parameter generator isprogrammed to determine the baseline injection protocol on the basis ofone or more criteria inputted by an operator.
 28. The injection systemof claim 25, wherein the parameter generator is programmed to determinethe flow rate of the pharmaceutical fluid to be injected during at leastthe first phase by dividing the volume of the pharmaceutical fluid to beinjected during the first phase by an injection duration of the firstphase.